Synthesis and evaluation of 5, 6-dihydro-8 <i>H</i> -isoquinolino[1, 2- <i>b</i> ]quinazolin-8-one derivatives as novel non-lipogenic ABCA1 up-regulators with inhibitory effects on macrophage-derived foam cell formation

Increasing the expression of ATP-binding cassette transporter A1 (ABCA1) can lower cellular cholesterol levels and prevent foam cell formation. In this study, a series of 5, 6-dihydro-8<i>H</i>-isoquinolino[1, 2-<i>b</i>]quinazolin-8-one derivatives were synthesised and assessed for their ability to up-regulate ABCA1 expression. The structure-activity relationship was explored and summarised. Among the 28 derivatives, compound <b>3</b> exhibited the most potent activity in activating the ABCA1 promoter (2.50-fold), significantly up-regulating both ABCA1 mRNA and protein levels in RAW264.7 macrophage cells. Mechanism studies revealed that compound <b>3</b> acted by targeting the LXR-involved pathway. In a foam cell model, compound <b>3</b> reduced ox-LDL-induced lipid accumulation and thereby inhibited foam cell formation. Moreover, compared to the LXR agonist T0901317, compound <b>3</b> led to minimal accumulation of unwanted lipids and triglycerides in HepG2 cells. With little cytotoxicity towards all the tested cell lines, compound <b>3</b> holds promise as a novel potential anti-atherogenic agent for further exploration.